Total synthesis of the utero-evacuant substance D,L-zoapatanol

ABSTRACT

A method of synthesizing 2S*, 3R*-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol, one of the active ingredients in the zoapatle plant, is described. The natural product is useful as a utero-evacuant agent.

The zoapatle plant is a bush about 2 meters high that grows wild inMexico. Botanically, it is known as montanoa tomentosa according toCervantes, Fam. Compositae, Tribe Heliantheae; another variety of thespecies is Montanoa fluoribunda. The plant is described in great detailin Las Plantas Medicinales de Mexico, Third Edition, Ediciones Botas(1944).

The plant has been used for centuries in the form of a "tea" or othercrude aqueous preparations primarily as a labor inducer or mensesinducer for humans. Its use as a utero-evacuant has been documented inthe literature.

In U.S. Pat. No. 4,086,358, a method is described for the isolation ofthe active ingredients in the zoapatle plant. One of the activeingredients is2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.This compound, referred to as zoapatanol, has the following structuralformula: ##STR1##

The present invention relates to a method for the total synthesis of2S*,3R*-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.Many of the intermediates employed in the synthesis of zoapatanol arenovel compounds and are included as part of the invention.

The synthesis is comprised of several steps which are summarized in thefollowing schematic diagram: ##STR2##

Wherein M is a protecting group selected from the group consisting of anO-tetrahydropyranyl group and an O-ethoxyethyl group, R is an acyl grouphaving 2-5 carbon atoms and X is selected from the group consisting ofbromo, chloro, iodo, tosyl, mesyl and brosyl.

As seen from the diagram, the first step in the synthesis involves thepreparation of the Grignard reagent (2) from the corresponding halocompound 8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene(1). For purposes of describing the invention, the process will bedescribed using a 2-tetrahydropyranyl group as the protecting group. Thereaction with magnesium is carried out in the standard fashion,preferably in an organic solvent such as ether or tetrahydrofuran. TheGrignard reagent is preferably used in the next step without isolation.

The coupled product (3) is prepared by reacting the Grignard reagentwith a substituted 6,7-oxido-2-octen-1-ol. The reaction is carried outin an organic solvent such as ether or tetrahydrofuran at a temperaturebetween about -20° and 0° C. It is preferred to carry out the reactionin the presence of a catalytic amount of a copper salt such as, forexample, cuprous iodide, cuprous bromide and lithium copper chloride.The coupled product (3) can be used directly in the cyclization step orit can be purified first by converting it to the diacyl derivative (4)by reaction with a suitable acylating agent such as acetic anhydride ina base such as pyridine.

The product obtained from the coupling reaction (3) is then converted toa mixture of epimeric oxepanes (5) upon treatment with a catalyticamount of a Lewis acid such as boron trifluoride etherate, aluminumchloride, and zinc chloride, for example, or a protic acid such asp-toluenesulfonic acid and trifluoroacetic acid. The reaction may becarried out in an organic solvent such as ether or tetrahydrofuran, forexample, at a temperature between about 0° and 30° C. The mixture ofoxepanes can also be prepared from the diacyl derivative (4) by firsthydrolyzing the ester groups with a mild base such as potassiumcarbonate, for example, and then reacting the product of the hydrolysiswith a Lewis acid.

The mixture of epimeric oxepanes (5) is converted to a mixture of diacylderivatives (6 and 7) by reaction with an acylating agent such as, forexample, acetic anhydride, propionic anhydride or butyric anhydride andacyl halides, such as for example, acetyl chloride, propionyl chlorideand butyryl chloride in a basic medium such as pyridine. The mixture ofdiacyl derivatives is separated by physical means prior to the nextstep. A preferred method of separation is preparative thin layerchromatography on a suitable adsorbent such as silica gel, alumina orflorisil. However, any suitable method of separating the epimericcompounds may be employed. Other suitable methods include columnchromatography and high pressure liquid chromatography. The compoundsare epimeric at the 3-position.

Hydrolysis of the tetrahydropyranyl derivative (6) to the hydroxylcompound (8) is accomplished by treating the tetrahydropyranylderivative with an acidic solvent system. Suitable acidic solventsystems include tetrahydrofuran-water-acetic acid,acetonitrile-water-acetic acid, and tetrahydrofuran-water-sulfuric acid.

The acylated derivative (8) is then converted to the derivatizedutero-evacuant material (9) by treatment with a suitable oxidizing agentsuch as, for example, chromium trioxide-sulfuric acid, chromiumtrioxide-acetic acid or chromium trioxide-pyridine. The oxidation ispreferably carried out in a suitable organic solvent such as acetone,2-butanone, chloroform or methylene chloride. The particular solventemployed will depend upon the particular oxidizing agent employed in theoxidation step. The residue obtained from the oxidation reaction is thenconverted to the underivatized utero-evacuant material (10) byhydrolysis with a suitable base such as, for example, sodium hydroxide,potassium hydroxide, potassium carbonate and tetra n-butyl ammoniumhydroxide. The hydrolysis step is preferably carried out in an organicsolvent such as, for example, methanol, ethanol, isopropanol, benzene,ether and tetrahydrofuran. However, aqueous media may also be employedfor the hydrolysis step. The reaction is preferably carried out in aninert atmosphere such as, for example, nitrogen or argon. The reactionis generally carried out at room temperature although elevatedtemperatures such as the reflux temperature of the solvent, for example,may also be employed. The crude product of the hydrolysis can be furtherpurified by column chromatography over an adsorbent material, such assilica gel, alumina or florisil.

The bromo compound,8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene, used toprepare the Grignard reagent in the first step in the synthesis isprepared by a series of reactions using 5-bromo-2-methyl-2-pentene asthe starting material. The bromide is first converted to2-methyl-5-nitro-2-pentene by reaction with sodium nitrite indimethylsulfoxide. The nitro compound is then reacted with methylcrotonate to form methyl 3,7-dimethyl-4-nitro-6-octenoate. Reaction ofthe octenoate derivative with titanous chloride results in theformulation of the oxo compound, methyl 3,7-dimethyl-4-oxo-6-octenate.The oxo compound is then reacted with lithium aluminum hydride to form3,7-dimethyl-4-hydroxy-6-octen-1-ol. The diol is converted to themono-acetate by reaction with acetic anhydride and the mono-acetate isthen converted to the tetrahydropyranyl derivative by reaction withdihydropyran. The tetrahydropyranyl derivative is converted to thecorresponding alcohol by reaction with potassium carbonate in a mixtureof methanol and water. The bromo compound is then obtained by reactingthe alcohol 3,7-dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octen-1-olwith phosphorous tribromide or triphenylphosphine and carbontetrabromide.

The substituted 6,7-oxido-2-octen-1-ol compound employed to prepare thecoupled product (3) is itself prepared by a series of reactions usingmyrcene as the starting material.8-Hydroxy-7-methyl-3-methylene-1,6-(E)-octadiene is first synthesizedfrom myrcene by the method of G. Buchi and H. Wuest, Helv. Chim. Acta,50, 2440 (1967). The octadiene compound is then converted to the hydroxyepoxide by reaction with a peracid such as m-chloroperbenzoic acid orperacetic acid. The hydroxy epoxide is then converted to the diacylderivative by reaction with an equivalent amount of a halogen, such asbromine, followed by an excess of an acetate salt, such as potassiumacetate. The major product of the reaction is the compound having the Econfiguration, however, about 20% of the compound having the Zconfiguration is also formed. Treatment of the diacyl derivative with aslight excess of p-toluenesulfonyl chloride in the presence of a baseaffords the corresponding tosylate. Reaction of the tosylate withpotassium bromide or sodium bromide in 2-butanone at reflux temperaturegives the corresponding bromo derivative. The tosylate or the bromidederivative is then hydrolyzed to the diol,7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol or7-methyl-3-hydroxymethyl-6,7-oxido-8-bromo-(E)-2-octen-1-ol by treatmentwith a base such as sodium hydroxide, potassium carbonate ortetra-n-butyl ammonium hydroxide. During the workup of the reactionmixture, the compound having the Z configuration forms a complex withmagnesium sulfate which results in a product having only the Econfiguration. Those compounds wherein X is brosyl and mesyl areprepared in the same manner in which the corresponding tosylate isprepared except that p-bromotoluenesulfonyl chloride and methanesulfonylchloride are employed in place of p-toluenesulfonyl chloride. Thecompound (1) wherein M is O-ethoxyethyl is prepared in the same manneras the compound wherein M is O-tetrahydropyranyl except that ethylvinylether is employed in place of dihydropyran.

The following examples describe the invention in greater detail and areintended to be a way of illustrating and not limiting the invention.

EXAMPLE I 8-Hydroxy-7-methyl-3-methylene-6,7-oxido-1-octene

A solution of sodium acetate (25 g, 0.03 m) in 40% peracetic acid (85ml) is added to a mixture of8-hydroxy-7-methyl-3-methylene-1,6-(E)-octadiene (50.0 g, 0.33 m),sodium carbonate (42.4 g, 0.40 m) and methylene chloride (500 ml) at 0°.The resulting mixture is allowed to come to room temperature and isstirred for an additional hour after which it is filtered, diluted withmethylene chloride (1 l) and washed with 5% sodium bicarbonate (2 l).The organic layer is dried (Na₂ SO₄), and evaporated in vacuo to givethe crude product (49.5 g).

The crude product is purified by column chromatography on silica gel(600 g; ethyl acetate/hexane 1:9) to give8-hydroxy-7-methyl-3-methylene-6,7-oxido-1-octene (23.2 g, 42%), ir(neat): 3448, 1592 cm⁻¹ ;

nmr (CDCl₃) δ: ##STR3##

EXAMPLE 21-Acetoxy-8-hydroxy-7-methyl-3-acetoxymethyl-6,7-oxido-(E)-2-octene

Bromine (56.8 g, 0.355 m) is added to a solution of8-hydroxy-7-methyl-3-methylene-6,7-oxido-1-octene (59.7 g, 0.355 m) inmethylene chloride (1 l) under nitrogen at 0°. The resulting mixture isallowed to warm to room temperature and then washed with water (500 ml).The organic layer is dried (Na₂ SO₄) and the solvent is removed to givethe crude dibromide (117.0 g).

A portion of this crude dibromide (57.2 g) in carbon tetrachloride (50ml) is added to a solution of potassium acetate (59.8 g, 0.61 m) andadogen 464 (15.0 g) in water at 60°. The resulting mixture is stirredovernight, after which it is cooled to room temperature, diluted withether (1 l) and washed with water (500 ml). The organic layer is dried(Na₂ SO₄) and evaporated in vacuo to give crude diacetate (64.0 g). Thecrude product is further purified by column chromatography on silica gel(2 kg, ethyl acetate/hexane 4:6) to give1-acetoxy-8-hydroxy-7-methyl-3-acetoxymethyl-6,7-oxido-(E)-2-octene (9.5g; 18%).

ir (neat) 3484, 1730 cm⁻¹ ; nmr (CDCl₃) δ: ##STR4##

EXAMPLE 31-Acetoxy-7-methyl-3-acetoxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octene

Triethylamine (10 ml) and tosyl chloride (13.78 g, 0.072 m) are added toa solution of1-acetoxy-8-hydroxy-7-methyl-3-acetoxymethyl-6,7-oxido-(E)-2-octene(10.34 g, 0.036 m) in dry tetrahydrofuran (300 ml). The resultingmixture is stirred at room temperature under nitrogen for 6 days. Themixture is then diluted with ether (800 ml) and washed with 5% sodiumbicarbonate (800 ml) and water (800 ml). The organic layer is dried (Na₂SO₄) and evaporated in vacuo to give the crude product (18.3 g). Thecrude material is purified by column chromatography on silica gel (600g; ethyl acetate/hexane; 40:60) to give1-acetoxy-7-methyl-3-acetoxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octene(10.12 g, 64%).

ir (neat) 1730, 1595 cm⁻¹ ; nmr (CDCl₃) δ: ##STR5##

EXAMPLE 4 7-Methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol

A mixture of1-acetoxy-7-methyl-3-acetoxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octene(4.0 g, 9.1 mmole), methanol (150 ml), water (5 ml) and saturatedpotassium carbonate solution (5 ml) is stored at room temperature for 2hours. Most of the methanol is then removed in vacuo and the resultingmixture is extracted with ethyl acetate (3×20 ml). The combined organiclayer is dried (MgSO₄) and evaporated in vacuo to give an oil (3.4 g).The crude oil is further purified by column chromatography on silica gel(20 g, isopropanol/chloroform 2:98) to give7-methyl-3-hydroxymethyl-6,7-oxido-8-toxyloxy-(E)-2-octen-1-ol as acolorless oil (2.24 g, 69%).

ir (neat) 3424, 1597 cm⁻¹ ; nmr (CDCl₃) δ: ##STR6##

EXAMPLE 5 2-Methyl-5-nitro-2-pentene

5-Bromo-2-methyl-2-pentene (120 g, 0.736 m) is added dropwise to asolution of sodium nitrate (60.9 g, 0.883 m) in dimethylsulfoxide (700ml) at room temperature under nitrogen. The mixture is stirred for 1hour and treated with water (500 ml) and petroleum ether (1 l). Theorganic layer is dried (Na₂ SO₄) and evaporated in vacuo to give a paleyellow liquid (80.7 g). This material is purified by columnchromatography on silica gel (800 g, petroleum ether) to give2-methyl-5-nitro-2-pentene as a colorless liquid (45.4 g, 48%).

ir (neat) 1550 cm⁻¹ ; nmr (CDCl₃) δ: 1.70 and 1.73 (both 0,6H, (CH₃)₂C═C<), 2.5˜2.93(m, 2H, CH₂ 4.35 (t, J=8 Hz, 2H, --CH₂ --CH₂ --NO₂),##STR7##

EXAMPLE 6

Methyl 3,7-Diazabicyclo[5,4,0]undec-5-ene (4 ml) is added to a solutionof 2-methyl-5-nitro-2-pentene (25.0 g, 0.193 m) in methanol (200 ml).The resulting mixture is heated to 60° and methyl crotonate (30.85 g,0.308 m) is added under nitrogen. The mixture is then stirred for 6 daysat 60° after which it is cooled to room temperature and most of themethanol is removed in vacuo. The residue is treated with ether (500 ml)and washed with 2 N HCl (250 ml) and water (250 ml). The organic layeris dried (Na₂ SO₄) and evaporated in vacuo to give 42.5 g of crudeproduct. The crude product is purified by column chromatography onsilica gel (500 g, ethyl acetate/hexane 2:98) to give methyl3,7-dimethyl-4-nitro-6-octenoate (8.65 g, 42%).

ir (neat): 1736, 1547 cm⁻¹ ; nmr (CDCl₃) δ: ##STR8##

EXAMPLE 7 Methyl 3,7-dimethyl-4-oxo-6-octenoate

A solution of methyl 3,7-dimethyl-4-nitro-6-octenoate (24.55 g, 0.107 m)in methanol (10 ml) is added dropwise to a solution of sodium methoxide(6.37 g, 0.118 m) in methanol (250 ml) at room temperature undernitrogen. The mixture is stirred for 1 hour, added to a mixture of 20%titanous chloride (170 ml, 0.267 m) and pH 7 buffer (potassium phosphatemonobasicsodium hydroxide buffer) solution (340 ml). The resultingmixture is stirred for 30 minutes after which it is treated with ether(1 l). The organic phase is separated, dried (Na₂ SO₄) and evaporated invacuo to give the crude product (15.4 g). This material is purified bycolumn chromatography on silica gel (300 g, 2% ethyl acetate in hexane)to give methyl 3,7-dimethyl-4-oxo-6-octenoate as a colorless liquid (6.8g, 35%). ir (neat) 1705 and 1735 cm⁻¹ ; nmr (CDCl₃) δ: ##STR9##

EXAMPLE 8 3,7-Dimethyl-4-hydroxy-6-octen-1-ol

Methyl 3,7-dimethyl-4-oxo-6-octenoate (68 g, 34 mmole) in ether (10 ml)is added to a mixture of lithium aluminum hydride (1.3 g, 34 mmole) andether (150 ml) at 0°. After the addition is complete the mixture isallowed to warm to room temperature and stirred for 1 hour, after whichit is cooled to 0° and carefully added to a 5% aqueous sodiumbicarbonate solution (50 ml). The resulting mixture is treated withwater (100 ml) and ethyl acetate (300 ml). The organic phase isseparated, dried (Na₂ SO₄) and the solvent is removed in vacuo to give acolorless oil (50.6 g, 94%). This material shows one spot on TLC (silicagel 50% ethyl acetate in hexane) and is not further purified.

ir (neat) 3225 cm⁻¹.

EXAMPLE 9 8-Acetoxy-2,6-dimethyl-5-hydroxy-2-octene

A mixture of 3,7-dimethyl-4-hydroxy-6-octen-1-ol (5.06 g, 29 mmole),acetic anhydride (3.06 g, 30 mmole), pyridine (4.75 g, 60 mmole) andether (100 ml) is stirred at room temperature for 16 hours. Theresulting mixture is treated with ether (200 ml) and washed withsaturated cupric sulfate solution (2×100 ml). The organic phase is dried(Na₂ SO₄) and evaporated in vacuo to give8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene as a colorless oil (2.27 g,45%).

ir (neat) 3508; 1738 cm⁻¹ ; nmr (CDCl₃) δ: ##STR10##

EXAMPLE 108-Acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene

A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene (2.27 g, 10.6mmole), dihydropyran (0.98 g, 11.4 mmole), p-toluenesulfonic acidmonohydrate (catalytic amount) and ether (50 ml) is stirred at roomtemperature for 16 hours. The resulting mixture is treated with ether(150 ml) and washed with 5% sodium bicarbonate solution (2×100 ml). Theorganic phase is dried (Na₂ SO₄), and evaporated in vacuo to give thecrude product (3.27 g). This material is further purified by columnchromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give8-acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene as acolorless oil (2.67 g, 89%).

ir (neat) 1739 cm⁻¹ ; nmr (CDCl₃) δ: ##STR11##

EXAMPLE 11 3,7-Dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octen-1-ol)

A mixture of8-acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene (2.67 g,0.5 mmole), saturated potassium carbonate solution (9 ml), water (6 ml)and methanol (100 ml) is stirred for 3 hours at room temperature. Mostof the methanol is removed in vacuo and the residue is treated withethyl acetate (500 ml) and water (200 ml). The organic phase is dried(Na₂ SO₄) and evaporated in vacuo to give the crude product (2.5 g).This material is further purified by column chromatography on silica gel(25 g, 15% ethyl acetate in hexane) to give3,7-dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octen-1-ol as a colorlessoil (1.5 g, 60%).

ir (neat) 3434 cm⁻¹, nmr (CDCl₃) δ: ##STR12##

EXAMPLE 12 8-Bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene

Triphenylphosphine (1.83 g, 7.02 mmole) in methylene chloride (30 ml) isadded to a mixture of3,7-dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octen-1-ol (1.20 g, 4.7mmole), carbon tetrabromide (1.94 g, 5.85 mmole), pyridine (2 ml) andmethylene chloride (30 ml) at 0° under nitrogen. The mixture is allowedto warm to room temperature and stirred for 4 hours, after which it istreated with methylene chloride (100 ml) and washed with 5% sodiumbicarbonate solution. The organic phase is dried (Na₂ SO₄) andevaporated in vacuo to give the crude product (5.6 g). This material isfurther purified by column chromatography on silica gel (100 g, 2% ethylacetate in hexane) to give8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene as acolorless oil (0..7 g, 46%).

nmr (CDCl₃) δ: ##STR13##

EXAMPLE 13 3,7-Dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octenylmagnesium bromide

The Grignard reagent is prepared from8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene (8.5 g,26.7 mmole) and magnesium (650 mg, 27.1 mmole) in tetrahydrofuran (35ml) at room temperature under argon. The reagent is not isolated but isused directly in the next step.

EXAMPLE 141-Acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[2-(tetrahydropyran-2-yloxy)]-(E)-2,14-hexadecadiene

An excess of the Grignard reagent is added to a solution of7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol (423.3mg, 1.3 mmole) in tetrahydrofuran at 0°, followed by Li₂ CuCl₄ (0.1mmole) and the mixture is stirred for 1.5 hours at 0°. The mixture isallowed to warm to room temperature and then treated with ice water (125ml) and ethyl acetate (400 ml). The organic phase is separated, dried(Na₂ SO₄) and evaporated in vacuo to give the crude product. Thismaterial is then treated with acetic anhydride (10 ml) and pyridine (2ml) and stirred for 16 hours at room temperature. The resulting mixtureis treated with ether (100 ml) and then washed with saturated cupricsulfate solution (100 ml) and 5% sodium bicarbonate solution (100 ml).The organic phase is dried (Na₂ SO₄) and evaporated in vacuo to give anoil (210 mg) which is further purified by column chromatography onsilica gel (7 g, 7% ethyl acetate in hexane) to give1-acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[2-(tetrahydropyran-2-yloxy)]-(E)-2,14-hexadecadieneas a colorless oil (41 mg, 9%).

ir (neat) 1735 cm⁻¹ ; nmr (CDCl₃) δ: ##STR14##

EXAMPLE 152S*,3R*-3-Acetoxy-6E-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl]oxepaneand2S*,3S*-3-acetoxy-6E-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-yloxy-7-nonenyl]-oxepane

A mixture of1-acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[2-(tetrahydropyran-2-yloxy)]-(E)-2,14-hexadecadiene(10 mg, 0.02 mmole), methanol (5 ml), saturated potassium carbonatesolution (1 ml) and water (1 ml) is stirred at room temperature for 3hours. The mixture is then treated with ethyl acetate (15 ml) and water(15 ml). The organic phase is dried (Na₂ SO₄) and the solvent is removedin vacuo to give3-hydroxymethyl-6,7-oxido-12-[2-(tetrahydropyran-2-yloxy)]-7,11,15-trimethyl-(E)-2,14-hexadecadiene-1-olas a colorless oil. The oil is dissolved in ether (5 ml), treated withboron trifluoride etherate (5 drops) and stirred for 90 minutes at roomtemperature. The resulting mixture is treated with pyridine (2 ml) andacetic anhydride (1 ml) and stirred for 16 hours. Most of the solvent isevaporated in vacuo and the residue (15 mg) is purified by columnchromatography on silica gel (1 g, 20% ether in petroleum ether to givea mixture of2S*,3R*-3-acetoxy-6E-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydro-2-yloxy)-7-nonenyl]-oxepaneand2S*,3S*-acetoxy-6E-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl]-oxepaneas a colorless oil (2 mg, 20%). The mixture of compounds is separated bypreparative thin layer chromatography (silica gel, 30% ethyl acetate inhexane).

EXAMPLE 162S*3R*-3-Acetoxy-6E-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

2S*,3R*-3-Acetoxy-6E-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane(2 mg, 0.02 mmole) in tetrahydrofuran (2 ml), water (0.3 ml) and glacialacetic acid (2 drops) is heated at 65° (bath temperature) in awell-capped test tube for 2 hours. The mixture is allowed to cool toroom temperature and is treated with ether (10 ml) and water (3 ml). Theorganic phase is dried (Na₂ SO₄) and the solvent is removed in vacuo togive a colorless oil (1.5 mg). The oil is homogeneous as determined bythin layer chromatography analysis (30% ethyl acetate in hexane).

ir (neat); 3497, 1739 cm⁻¹ ; nmr (CDCl₃) δ; ##STR15##

EXAMPLE 172S*,3R*-6E-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol

A.2S*,3R*-3-Acetoxy-6E-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(333 mg) is dissolved in acetone (5 ml) and treated slowly with Jonesreagent (2 mmole) at 0° under nitrogen. The resulting mixture is stirredfor 7 minutes and then treated with ether (30 ml) and water (20 ml). Thelayers are separated and the aqueous layer is extracted with ether (20ml). The combined organic layer is washed with water (30 ml). dried(MgSO₄) and evaporated in vacuo to give an oil. The crude product isused as such in the next step.

B. The crude product obtained above (161 mg) is dissolved intetrahydrofuran (5 ml) and water (5 ml). To this mixture, tetra n-butylammonium hydroxide (20% solution in methanol, 1 ml) is added undernitrogen at room temperature and the resulting mixture is stirred for 40hours. The mixture is treated with ether (50 ml) and the organic layeris washed with 10% hydrochloric acid (2×15 ml), dried (MgSO₄) andevaporated in vacuo to give an oil. This crude product is purified bychromatography on a SilicAR column (5 g).2S*,3R*-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(81.8 mg) is eluted with ether. Its ir, nmr spectra, R_(f) on thin layerand retention time on gas chromatography are identical to those of thenatural product (Compound I) reported in U.S. Pat. No. 4,086,358. Thecompound has the following physical analysis:

ir (neat) μ: 2.91 and 5.88.

nmr _(TMS) ^(CDCl).sbsp.3 δ: ##STR16##

Mass spec [m/e]: 320 [M-18], 251, 233, 221, 171, 143, 141, 137, 125,113, 97, 95, 81, 69.

Chemical Ionization: M⁺ +H=339; M.W.=338.

EXAMPLE 18 8-Acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene

A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene (2.27 g, 10.6mmole), ethyl vinylether (0.82 g. 11.4 mmole), p-toluenesulfonic acidmonohydrate (catalytic amount) and ether (50 ml) is stirred at roomtemperature for 16 hours. The resulting mixture is treated with ether(150 ml) and washed with 5% sodium bicarbonate solution (2×100 ml). Theorganic phase is dried (Na₂ SO₄), and evaporated in vacuo to give thecrude product. The crude material is further purified by columnchromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.

EXAMPLE 19 3,7-Dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol

A mixture of 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene (0.5mmole), saturated potassium carbonate solution (9 ml), water (6 ml) andmethanol (100 ml) is stirred for 3 hours at room temperature. Most ofthe methanol is removed in vacuo and the residue is treated with ethylacetate (500 ml) and water (200 ml). The organic phase is dried (Na₂SO₄) and evaporated in vacuo to give the crude product. This material isfurther purified by column chromatography on silica gel (25 g, 15% ethylacetate in hexane) to give3,7-dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol as a colorless oil.

EXAMPLE 20 8-Bromo-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene

Triphenylphosphine (1.83 g, 7.02 mmole) in methylene chloride (30 ml) isadded to a mixture of 3,7-dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol(4.7 mmole) carbon tetrabromide (1.94 g, 5.85 mm), pyridine (2 ml) andmethylene chloride at 0° C. under nitrogen. The resulting mixture isallowed to warm to room temperature and stirred for 4 hours after whichit is treated with methylene chloride (100 ml) and washed with 5% sodiumbicarbonate solution. The organic phase is dried and evaporated in vacuoto give the crude product. This material is further purified by columnchromatography on silica gel (100 g, 2% ethyl acetate in hexane) to give8-bromo-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.

EXAMPLE 211-Acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[(1-ethoxyethoxy)]-(E)-2,14-hexadecadiene

The Grignard reagent is prepared from8-bromo-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene (26 mmole) andmagnesium (27.1 mmole) in tetrahydrofuran (35 ml) at room temperatureunder argon. An excess of the Grignard reagent is added to a solution of7-methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-(E)-2-octen-1-ol (423.3mg, 1.3 mmole) in tetrahydrofuran at 0° C., followed by Li₂ CuCl₄ (0.1mmole) and the mixture is stirred for 1.5 hours at 0°. The mixture isallowed to warm to room temperature and then treated with ice water (125ml) and ethyl acetate (400 ml). The organic phase is separated, dried(Na₂ SO₄) and evaporated in vacuo to give the crude product. Thismaterial is then treated with acetic anhydride (10 ml) and pyridine (2ml) and stirred for 16 hr. at room temperature. The resulting mixture istreated with ether (100 ml) and then washed with saturated cupricsulfate solution (100 ml) and 5% sodium bicarbonate solution (100 ml).The organic phase is dried (Na₂ SO₄) and evaporated in vacuo to give anoil which is further purified by column chromatography on silica gelPG,22 (7 g, 7% ethyl acetate in hexane) to give1-acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[(1-ethoxyethoxy)](E)-2,14-hexadecadieneas a colorless oil.

What is claimed is:
 1. The process for the preparation of a compound ofthe formula ##STR17## which comprises reacting a compound of the formula##STR18## with magnesium to provide a Grignard reagent of the formula##STR19## reacting the Grignard reagent with a compound of the formula##STR20## to produce a compound of the formula ##STR21## and reactingthe product with a Lewis acid or a protic acid to produce a compound ofthe formula ##STR22## reacting the product with an acylating agent toproduce a compound of the formula ##STR23## reacting the acylatedproduct with an acid to produce a compound of the formula ##STR24##reacting the product with an oxidizing agent to form a compound of theformula ##STR25## and hydrolyzing the product with a base, wherein R isan acyl group having 2-5 carbon atoms, M is an tetrahydropyran-2-yloxyor 1-ethoxyethoxy group, and X is bromo, chloro, iodo, tosyl, mesyl andbrosyl.
 2. The process of claim 1 wherein the Lewis acid is borontrifluoride etherate.
 3. The process of claim 1 wherein the protic acidis p-toluenesulfonic acid.
 4. The process of claim 1 wherein theacylating agent is acetic anhydride.
 5. The process of claim 1 whereinthe oxidizing agent is chromium trioxide-sulfuric acid.
 6. The processof claim 1 wherein the base is tetra n-butyl ammonium hydroxide.
 7. Theprocess of claim 1 wherein M is tetrahydropyran-2-yloxy.
 8. The processof claim 1 wherein X is tosyl.